Gemcitabine (1; marketed as Gemzar®) is an effective nucleoside analogue that is currently approved to treat breast, non-small cell lung, ovarian and pancreatic cancers and widely used to treat a variety of other cancers including bladder, biliary, colorectal and lymphoma.

Gemcitabine's clinical utility is limited by a number of inherent and acquired resistance mechanisms. At the cellular level resistance is dependent on three parameters: (i) the down-regulation of deoxycytidine kinase, necessary for the activation into the phosphorylated moiety; (ii) the reduced expression of nucleoside transporters, in particular, hENT1 required for uptake by cancer cells; and (iii) the up-regulation of catalytic enzymes especially cytidine deaminase that degrades gemcitabine.
WO2005/012327 describes a series of nucleotide prodrugs for gemcitabine and related nucleoside drug molecules. Among them gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) is identified as a particularly effective compound.
These prodrugs appear to avoid many of the inherent and acquired resistance mechanisms which limit the utility of gemcitabine (Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development'; Slusarczyk et all; J. Med. Chem.; 2014, 57, 1531-1542).
NUC-1031 2 is prepared as a mixture of two diastereoisomers, epimeric at the phosphate centre.

Unfortunately, NUC-1031 2 is extremely lipophillic and thus poorly water soluble (by calculation: <0.1 mg/mL), and the ionisable moieties, pyrimidine nitrogen and phenolic hydroxyl have calculated pKas that lie out-side the pH range suitable for parenteral administration. It is essentially insoluble in water, regardless of salt content or pH, and this has implications for the development of formulations for delivering the prodrug at sufficiently high dosages for effective treatment. It also has implications for the development of efficient manufacturing processes which will allow NUC-1031 to be produced cost effectively.
It is an aim of certain embodiments of this invention to provide gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) in a form which can be formulated into a effective pharmaceutical composition.
It is also an aim of certain embodiments of this invention to provide a form of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) which can be prepared and stored for an extended period of time.
It is an aim of certain embodiments of this invention to provide gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) in a form which has a higher solubility than prior art forms.
It is an aim of certain embodiments of this invention to provide gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2) as a single diastereoisomer at phosphorus.
Certain embodiments of this invention satisfy some or all of the above aims.
The gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate of the current invention is preferably of substantially the same activity as gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031; 2). It may, however, have slightly lower activity but have other benefits as described in this specification if there is a manufacturing or therapeutic benefit to the use of it in this form.